pH sensitive polymers for oral drug delivery systems have been widely studied. These polymers can undergo reversible transformation from dissolved state to collapsed state and vice versa in response to variation in the pH of the gastrointestinal tract. The currently available pH sensitive polymers in the market are Eudragit L, Cellulose acetate phthalate, Cellulose acetate trimellitate, Hydroxypropyl methylcellulose phthalate, Hydroxypropyl methyl cellulose acetate succinate and Polyvinyl acetate phthalate. These polymers are not soluble under acidic pH condition and dissolve rapidly in neutral and alkaline media. They are being used as enteric coatings for the dosage forms which have to protect the drug at the acidic pH conditions in stomach. The rapid dissolution of the polymers at near neutral pH limits their utility in sustained release of drugs in intestine.
Many attempts have been made to develop new pH sensitive polymers for drug delivery applications. One of the approaches is the functional modification of natural and synthetic polymers to introduce pH sensitive behavior. References may be made to patent application U.S. Pat. No. 5,811,121, wherein Wu et al. disclosed a cellulose modification to obtain pH sensitive polymer. Acetoacetylation of cellulose resulted in a series of cellulose acetoacetate esters depending upon the degree of substitution. These polymers are claimed to be insoluble at acidic condition but dissolve readily at pH>7.5. The exact dissolution pH depends upon the degree of substitution.
References may be made to Journal “Xiaolin Lai, Chengdong Sun, Hua Tian, Wenjun Zhao and Lin Gao, International Journal of Pharmaceutics, 352, 66-73, 2008” wherein the modification of poly (styrene-alt-maleic anhydride) copolymer by partial esterification of carboxyl groups with ethanol have described. The modified polymer does not dissolve at pH<6.0 but dissolves readily at pH>6.4. Coating the polymer on erythromycin tablets suppressed the drug release at acidic pH condition and released rapidly at near neutral pH condition.
References may be made to patent application U.S. Pat. No. 4,983,401, wherein Eichel et al. modified the enteric polymer cellulose acetate phthalate with a stearyl chloride to control its dissolution at near neutral pH. The modified enteric polymer remained hydrophobic at pH found in the stomach and became hydrophilic but remained insoluble at intestinal pH condition. The problem associated with polymers comprising phthalate groups such as cellulose acetate phthalate, Hydroxypropyl methylcellulose phthalate and polyvinyl acetate phthalate is their storage stability. On storage the phthalate groups undergo hydrolysis and leave behind phthalic acid residues. This leads to unpredictable dissolution behavior of the polymer with respect to pH.
Hydrogels are the most frequently investigated systems for development of drug delivery systems. References may be made to Journal “Hasan Basan, Meneme Gümüderelĺo{hacek over (g)}lu and Tevfik Orbey, International Journal of Pharmaceutics, 245, 191-198, 2002” wherein a pH sensitive hydrogel for the sustained release of drugs is described. Copolymerization of acrylic acid, 2-Hydroxyethyl methacrylate and ethylene glycol dimethacrylate in the presence of drug diclofenac sodium provided a pH sensitive drug delivery device. However, the presence of cross linking renders these materials unsuitable for coating drugs.
References may be made to Journal “Yihong Huang, Huiqun Yu and Chaobo Xiao, Carbohydrate Polymers, 69, 774-783, 2007” wherein a polyelectrolyte hydrogel composition based on cationic guar gum and polyacrylic acid are described. An aqueous solution of cationic guar gum, acrylic acid monomer, drug and a photo initiator was exposed to the UV irradiation. The drug release was substantial in both acidic and neutral media.
References may be made to Journal “Mahaveer D. Kurkuri and Tejraj M. Aminabhavi, Journal of Controlled Release, 96, 9-20, 2004” wherein a pH sensitive polymer composition prepared in the form of microspheres using polyvinyl alcohol and polyacrylic acid interpenetrating network crosslinked with gluteraldehyde is described. The drug was incorporated during the preparation of microspheres. The microspheres swelled less at acidic pH condition than at near neutral pH condition. Hydrogels were prepared in the presence of drug. However, the solubility of drug within the monomer mixture, the drug stability, possible reaction between drug and reactive monomers during the polymerization and removal of unreacted monomers from the drug loaded hydrogels limited utility of these materials in the industry.
References may be made to Journal “Heung Soo Shin, So Yeon Kim and Young Moo Lee, J Appl Polym Sci 65, 685-693, 1997” wherein drug can also be loaded by soaking the purified hydrogel in the drug solution as described by Shin et al. A pH and thermosensitive interpenetrating network hydrogel was obtained by copolymerization of acrylic acid and methylene bis acrylamide in the presence of polyvinyl alcohol. The drug loading was achieved by imbibing the hydrogel in drug solution. The hydrogels could release 1.5-2.0 mg drug at pH 7.0 for the period of 25 hours.
References may be made to Journal “Oya Sipahigil, Ayla Gürsoy, Fulya akala{hacek over (g)}ao{hacek over (g)}lu and İmer Okar, International Journal of Pharmaceutics, 311, 130-138, 2006” wherein drug loading by soaking the pH sensitive crosslinked particles obtained by copolymerization of methacrylic acid and poly (ethylene glycol) monomethacrylate using tetra (ethylene glycol) dimethacrylate as a crosslinker. The drug loaded particles could suppress the drug release at pH 1.2, and release the drug up to 10 hours at the pH range of 5.8-7.4. However, the drug loading was only about 0.54 to 2.09% and could not be increased by increasing the drug concentration in the solution. Clearly such low drug loadings are not acceptable in pharmaceutical dosage forms as the amount of excipient needed would be very large and may not meet regulatory requirements.
It is evident from the above disclosures that the drug loading by imbibition method is not effective since the achievable drug loading is far less than the required drug content. The selection of medium for drug loading is limited, since the drug dissolution as well as hydrogel swelling has to be achieved to enhance the loading. Most importantly, the hydrogels are insoluble in solvents and they are not suitable for many of the process techniques to obtain diverse dosage forms. Drying of swollen hydrogels is energy consuming, limits production rates and influence drug stability adversely.
References may be made to Journal “Ricardo G. Sousa, Alberto Prior-Cabanillas, Isabel Quijada-Garrido and José M. Barrales-Rienda, Journal of Controlled Release, 102, 595-606, 2005” wherein copolymerized N-isopropyl acrylamide and methacrylic acid as a functional monomers and tetraethylene glycol dimethacrylate as a crosslinking agent. The drug was loaded by soaking the hydrogel in drug solution. The interaction between carboxyl groups present in the polymer and the cationic group of drug enhanced the loading up to 17%. The enhancement in drug loading would thus depend on the basicity of the drug. The system also suffers from all the limitations of a crosslinked polymer. References may be made to Journal “Jose M. Cornejo-Bravo, Maria E. Flores-Guillen, Eder Lugo-Medina and Angel Licea-Claverie, International Journal of Pharmaceutics, 305, 52-60, 2005” wherein Drug-polyelectrolyte complex composition is described. It is an ionic complex comprising poly carboxyalkyl methacrylate and cationic drug. About 75% drug loading was achieved by aqueous precipitation method. The drug release was suppressed at acidic pH condition and sustained at pH 7.4. As mentioned earlier, utility of such compositions is limited to specific drug-polymer systems.
References may be made to patent application U.S. Pat. No. 5,770,627, wherein the bioadhesive graft copolymer composition in for the topical drug delivery application is disclosed. involves preparation of hydrophobic macro monomer and copolymerizing same with acrylic acid to yield graft copolymer. The dissolution of the polymers in neutral and alkaline condition depends upon composition. However, the swelling or dissolution behaviour of the polymers at acidic pH condition was not disclosed. The formulations were developed by dissolving the polymer in phosphate buffer saline and mixing with cationic drug solution to yield drug-polyelectrolyte complex.
It is evident from the above descriptions that the drug loading can be enhanced by complexation of polyelectrolyte with drug. However, this approach is limited to systems wherein the polymer and drug contain opposite charges. There are numerous drugs which are nonionic in nature and can not form complex with the polymers.
There are some reports which describe the utilization of pH sensitive graft copolymer for the development of drug delivery systems. References may be made to Journal “Udaya S. Toti and Tejraj M. Aminabhavi, Journal of Controlled Release, 95, 567-577, 2004” wherein One such polymer composition is acrylamide grafted guar gum is described. Hydrolysis of polyacrylamide graft chains leads to polyacrylic acid graft chains. While the acrylamide grafted guar gum releases the drug diltiazem hydrochloride for 8 hours, acrylic acid grafted guar gum releases the drug up to 12 hours. The formulation comprising only drug and polymer showed the drug release up to 27% in 0.1 N HCL solution and rest of the drug was released in pH 7.4 phosphate buffer solution. The graft copolymer did not show pH dependent drug release.
References may be made to Journal “Meifang Huang, Xin Jin, Yu Li and Yue'e Fang, Reactive & Functional Polymers, 66, 1041-1046, 2006” wherein a pH sensitive graft copolymer composition is described. The polymer was prepared by grafting of acrylic acid monomer on the maleoylchitosan to obtain graft copolymers comprising various levels of acrylic acid. These polymers swelled at pH<4.0 as well as at higher pH 10, but deswelled in the pH range 6-8.
References may be made to Journal “Young Moo Lee, Sung Yoon Ihm, Jin Kie Shim, Jin Hong Kim, Chong Soo Cho and Yong Kiel Sung, Polymer, 36, 81-85, 1995” wherein a polymer composition which exhibited pH dependent permeability of the drug is described. The surface of the polyamide membrane was modified with functional monomers like acrylic acid and methacrylic acid using plasma polymerization and ultraviolet irradiation techniques. The permeation of membrane was studied using the drug riboflavin at various pH. The permeation of riboflavin decreased from pH 4-5 and 6-7 for the acrylic acid grafted and methacrylic grafted membranes respectively. This low permeability in the pH range 4-5 and 6-7 limits the application of this polymer in oral drug delivery where the pH of the gastrointestinal tract various from 1.8-7.4.
References may be made to Journal “Toshiyuki Shimizu, Shinya Higashiura and Masakatsu Ohguchi, Journal of Applied Polymer Science, 72, 1817-1825, 1999” wherein acrylic acid grafted polyester water dispersible coating composition obtained by grafting of acrylic acid on the fumaric unsaturation of polyester is described. The conversion of unsaturation after the grafting reaction was about 50%. Since the reactivity of acrylic acid monomer towards the fumaric unsaturation was low, ethylacrylate was used as a comonomer. Complete conversion of unsaturation was achieved. However, the achievable incorporation of acrylic acid was limited, since it was partially replaced by ethylacrylate. Also the unreacted unsaturated groups can lead to crosslinking during processing rendering these materials insoluble in solvents and hence can not be dissolved in solvents for coating the drugs.
References may be made to Journal “Toshiyuki Shimizu, Shinya Higashiura and Masakatsu Ohguchi, Journal of Applied Polymer Science, 74, 1395-1403, 1999” wherein in order to increase the incorporation of hydrophilic monomer, another approach was described. Styrene and maleic anhydride monomers were copolymerized with the unsaturated polyester. Eventhough, this approach could enhance the incorporation of hydrophilic monomer, the conversion of unsaturations present in the polyester was only upto 60% after the grafting reaction. It is known that polymers with free unsaturations are susceptible to undergo polymerization at any stage of processing which would result in crosslinking. Also, the pH dependent dissolution of these polymers and their utility in the development of drug delivery systems has not been reported.
It is evident from the above disclosures that the pH sensitive random copolymers like Eudragit L undergo rapid dissolution at near neutral pH while retaining its integrity under acidic pH conditions. The graft copolymers described in the above descriptions, do not undergo delayed dissolution in response to the variation of pH along the gastrointestinal tract. Therefore, there is a need for solvent soluble pH sensitive polymers which swell/dissolve in response to change of pH in the gastrointestinal tract. The present invention describes such polymer compositions.